Osteosarcoma, the most common primary malignancy of bone, is an aggressive cancer occurring predominantly in children and adolescents. Studies of familial cancer syndromes and sporadic cases have strongly implicated both p53 and pRb in osteosarcoma tumorigenesis. Thus, our lab created a fully penetrant mouse model of osteosarcoma based on the osteoblast-specific deletion of p53 and pRb. This model faithfully recapitulates the defining features of human OS, including pathology, metastatic behavior, and cytogenetic complexity and shares a transcriptional profile with the human disease. Using a genome-wide shRNA screen, we have identified gene products whose inhibition synergizes with p53 and pRb deletion to kill osteosarcoma cells. This screen identified genes that are required for proliferation and survival of osteosarcoma cell lines in an unbiased fashion. The screen identified a number of druggable gene products and pathways, including members of the HDAC family of histone deacetylases. Follow-up studies with selective chemical HDAC inhibitors and shRNAs against individual HDACs demonstrate that osteosarcoma cells are vulnerable to HDAC1, 2, 3, 5 and 7 inhibition. Selective inhibition of HDACs has emerged as a promising avenue toward cancer therapy, therefore we look to understand if and how HDAC inhibition can be used as a therapeutic approach to treating osteosarcoma.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4234. doi:1538-7445.AM2012-4234